Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000061639p
Ethics application status
Submitted, not yet approved
Date submitted
10/01/2023
Date registered
18/01/2023
Date last updated
20/01/2023
Date data sharing statement initially provided
18/01/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Single Centre, Randomized, Double Blind, Placebo Controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of NeuroDirect Ketamine in Healthy Adult Volunteers
Scientific title
A Phase 1, Single Centre, Randomised, Double Blind, Placebo Controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of NeuroDirect Ketamine in Healthy Adult Volunteers
Secondary ID [1] 308724 0
NIL
Universal Trial Number (UTN)
Trial acronym
PSYCH007
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post-traumatic stress disorder 328659 0
Condition category
Condition code
Mental Health 325669 325669 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a phase 1, randomised, double-blind, placebo-controlled study to investigate the safety, tolerability, and pharmacokinetics of topically administered NeuroDirect Ketamine in a single-ascending dose study in adult healthy volunteers between 18-60 years of age, to establish the recommended phase 2 dose (RP2D).
The study plans to test single doses of NeuroDirect Ketamine of 25 mg (Cohort 1), 50 mg (Cohort 2), and 100 mg (Cohort 3). The decision to progress from Cohort 1 to Cohort 2 and Cohort 2 to Cohort 3 will be based on safety and tolerability by the SRC. A similar sequence will follow for subsequent progression decisions by the SRC for all the cohorts.
Each cohort will consist of 8 participants (6 participants receiving NeuroDirect Ketamine and 2 participants receiving placebo).
1 ml of single dose of either study drug or placebo applied via topical administration to back of neck at the hairline and below between C3 and C4 vertebrae. The Investigator or designee is responsible for the education of study staff as to the correct administration of the study drug. Study staff will apply the product topically to the participant under direct supervision of Investigator.
Intervention code [1] 325190 0
Treatment: Drugs
Comparator / control treatment
Placebo glycerine based cream
Control group
Placebo

Outcomes
Primary outcome [1] 333518 0
To evaluate the safety and tolerability of NeuroDirect Ketamine following a single topical dose administration in healthy adult volunteers.
Timepoint [1] 333518 0
Safety and tolerability will be assessed based on:
• Frequency and severity of Treatment-Emergent Adverse Events and serous AEs (local and systemic) at all study visits.
• Heart rate, blood pressures at screening, D-1, Day1, Day2, Day3, Day4, Day5 and follow up visit on Day 12. ,
12- lead ECG - Performed at screening, On Day 1 ECG will be assessed at pre-dose and at 2, 6 and 12-hours post-dose. and then on Day2, Day3, Day4 and follow up visit on Day 12.
• Clinical laboratory safety tests ((hematology, biochemistry, coagulation, and urinalysis)) performed at screening, D-1, Day1, Day2, Day3, Day4, and follow up visit on Day 12.
• Brief Psychiatric Rating Scale (BPRS) assessment to monitor hallucinations as a safety parameter performed at screening, Day2, Day3, Day4, Day5 and follow up visit on Day 12.
Secondary outcome [1] 417394 0
• To characterise the pharmacokinetic (PK) properties of NeuroDirect Ketamine and its major metabolite norketamine in plasma, CSF, and urine following a single topical dose administration.
Timepoint [1] 417394 0
Blood sample for PK analysis will be collected at pre-dose and Post-dose 0.5, 1, 2, 4, 6, 8 and 12 hour on Day 1 and then at 24hr, 48hr, 72hr and 96hr.
Urine sample for PK analysis will be collected at pre-dose and Post-dose 1hr, 24hr, 48hr, 72hr and 96hr.
One CSF sample for PK analysis will be collected at 0.5 hour post dose.
Secondary outcome [2] 417547 0
To determine the maximum tolerated dose or the maximum feasible dose in the absence of establishing a maximum tolerated dose, and the recommended phase 2 dose of NeuroDirect Ketamine
Timepoint [2] 417547 0
PK parameters will be calculated as per scheduled timepoint following single dosing and will include the following:
o Maximum concentration (Cmax), time to reach Cmax (Tmax), area under the concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration (AUC0-last), AUC from time zero to time t (AUC0-t).
If the data are available, AUC from time zero to infinity (AUC0-inf), terminal elimination half-life (t1/2), apparent clearance (CL/F), and apparent volume of distribution (Vz/F).

Eligibility
Key inclusion criteria
To be eligible for this study, participants must meet all of the following inclusion criteria:
1. Healthy male or female volunteers aged between 18 to 60 years (inclusive) at the time of informed consent.
2. Capable of understanding the purposes and risks of the study and able to provide written informed consent before any study-specific screening procedures are performed.
3. Willing and able to adhere to all protocol requirements, including willingness to comply with scheduled visits.
4. Body weight = 50 kg, and a body mass index (BMI; Quetelet index) in the range 18.0 to 32.0, inclusive.
5. Subject is free from clinically significant (in the opinion of the Investigator) illness or disease as determined by their medical and surgical history, physical examination, 12-lead ECG, vital signs and clinical laboratory determinations.
6. Adequate venous access in both arms for collection of a number of blood samples.
7. Negative urine drug/alcohol breath testing at Screening and prior to randomisation. Note: Screening urine drug test/alcohol breath testing may be repeated once if deemed appropriate by the Investigator.
8. Must have a negative COVID-19 PCR test on Day -1
9. If a subject is undergoing vaccination against Covid 19 virus, must wait 14 days after vaccination before first dose of investigational drug.
10. Female participants must meet 1 of the following criteria:
a) Not of childbearing potential, defined as surgically sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy - verbal confirmation through medical history review acceptable) or postmenopausal (i.e., no menses for at least 12 months). Postmenopausal status is to be confirmed by testing follicle-stimulating hormone [FSH] levels or local practice.
b) Of childbearing potential and agrees to take effective contraceptive measures throughout the study period (i.e., highly effective birth control method such as hormonal contraception or intrauterine device [IUD], or abstinence, when in line with preferred or usual lifestyle), from study entry (i.e., Screening) until at least 3 months after the last dose of study drug. Contraception requirements do not apply for participants in an exclusively same-sex relationship.
c) Of childbearing potential and in an exclusive relationship with a partner who has had a bilateral vasectomy at least 6 months prior to study entry.
11. Male participant: has undergone bilateral vasectomy (at least 6 months prior to study entry) and has documented evidence of azoospermia at least 90 days post procedure. or agrees to use effective contraceptive effective contraceptive measures (i.e. condoms for all types of sexual intercourse; plus use of a highly effective birth control method by their female partner, if they are of childbearing potential [see Inclusion Criteria 10]; or abstinence, when in line with preferred or usual lifestyle) and not donate sperm throughout the study period from study entry (i.e., Screening) until at least 3 months after the last dose of study drug.
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
A participant who meets any of the following exclusion criteria must be excluded from the study:
1. History of severe allergic or anaphylactic reactions, known intolerance, allergy or hypersensitivity reactions to Ketamine.
2. History of coronary disease, peripheral vascular disease, cerebrovascular accident, transient ischaemic attack, uncontrolled hypertension or signs/symptoms of ischaemic heart disease.
3. Mean baseline blood pressure above 130/80 mm Hg.
4. History of neurologic conditions such as seizures or convulsive disorders (including epilepsy), severe head injury or increased intracranial pressure. A history of childhood febrile seizures is allowed.
5. Presence of current psychiatric condition or psychiatric condition requiring pharmacological management within the last 6 months.
6. Positive results of a screen for PTSD through a validated PTSD rating scale questionnaire
7. A calculated creatinine clearance of < 85 mL/minute at Screening or pre randomisation according to the equation using Cockcroft and Gault.
8. Liver function tests showing values for ALT or AST > 1.5 times ULN at Screening.
9. Evidence or history of clinically significant (in the opinion of the Investigator) other cardiovascular, pulmonary, neurologic or renal disorders or hepatic, gastrointestinal, oral (difficulty swallowing / taking oral medication), haematological, endocrine, or psychiatric impairment/disorders.
10. Have undergone surgery requiring or have received (for any reason) anaesthetic within 30 days of Day 1, or planned surgery during the study.
11. Use of CNS depressants including opioids, sedative, anxiolytics, hypnotics, neuroleptics, phenothiazines, tranquilisers, skeletal muscle relaxants, sedating antihistamines or cimetidine within 30 days of Day 1. Use of macrolide antibiotics (e.g., Erythromycin), azole antifungal agents (e.g., Ketoconazole) or protease inhibitors (e.g., Ritonavir) within 30 days of Day 1. Thirty-day washout from these medications is required.
12. Treatment with another investigational drug, investigational device, or approved therapy for investigational use within 1 month or 5 half-lives of the specific drug/biologic (whichever is longer) prior to dosing.
13. Donation or loss of more than 500 mL of blood within 30 days of Day 1 and/or plans to donate blood during the study.
14. Use of any prescription medication within 14 days of Day 1 and for duration of study, unless approved by both the Investigator and the Medical Monitor (in writing). If necessary, paracetamol (acetaminophen) or ondansetron (or other 5-HT3 receptor antagonist) may be administered with the approval of the Investigator.
15. Use of any over the counter product, herbal product, diet aid, or hormone supplement, with a particular regard to hemp or products containing cannabidiol, within 14 days of Day 1 and for duration of study, unless approved by both the Investigator and Medical Monitor (in writing).
16. Evidence or history of substance or alcohol abuse (drink more than 4 standard units of alcohol per day or >14 standard units per week), including positive results for the urine drugs of abuse test or a positive alcohol breath test at Screening or at Check-In (Day -1).
17. Unwilling or unable to abstain from recreational drug/substance use, from 48 hours before check-in until final study visit.
18. Consumption of grapefruit, grapefruit juice or any products containing CYP3A4 inhibitors and inducers within 14 days of Day 1 and through to completion of the study.
19. Subjects who are not willing or are unable to refrain from nicotine products or smoking 24 hours before check-in until completion of the confinement period.
20. History of significant alcohol abuse within 6 months of screening or any indication of regular use of more than 14 units of alcohol per week for female subjects and 21 units of alcohol per week for male subjects (1 unit is 360 mL of beer or 45 mL of alcohol 40%, or 150 mL of wine), and unwilling to refrain from consumption of alcohol from 24 hours before check-in until completion of the confinement period.
21. The use of more than 10 cigarettes, nicotine products per day or use of vaping device or e-cigarettes ten times per day within the past 30 days.
22. Unwilling or unable to abstain from caffeinated or other xanthine-containing products from check-in until completion of the confinement period.
23. Positive screening test for Human Immunodeficiency Virus (HIV) antibodies, Hepatitis B surface antigen or Hepatitis C antibody.
24. Malignancy within 5 years of screening visit (excluding non-melanoma skin cancer that has been resected).
25. Female subject that is pregnant or lactating.
26. Subject who is considered unsuitable for participating in the study in the opinion of the investigator.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed participant specific code break envelopes will be produced by the Sponsor and will be kept at the investigational site in a secure, accessible location.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A randomisation list will be prepared using a statistical software package by an independent Biostatistician
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Continuous variables will be summarised by dose and visit (where applicable), including the number of participants, mean, median, standard deviation, minimum, and maximum. Categorical endpoints will be summarised using the number of participants with frequency counts and percentages.
For each treatment plasma, CSF, and urine concentrations or ketamine and norketamine will be tabulated and summarised by treatment and nominal time using descriptive statistics which include, but are not limited to: number of subjects, arithmetic mean, standard deviation, coefficient of variation, geometric mean, median, minimum and maximum.
If analytical data permit, the following PK parameters for ketamine and norketamine will be calculated:
Cmax, Tmax, area under concentration-time curve (AUC), AUC0-last, AUC0-t, AUC0-inf, t1/2, CL/F. .

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
13/03/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
24
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 23790 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 39239 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 312943 0
Commercial sector/Industry
Name [1] 312943 0
Psycheceutical, Inc
Country [1] 312943 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Psycheceutical, Inc
Address
515 E. Las Olas Blvd
Suite 120
Fort Lauderdale, FL 33301
Country
United States of America
Secondary sponsor category [1] 314637 0
None
Name [1] 314637 0
Address [1] 314637 0
Country [1] 314637 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 312216 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 312216 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 312216 0
Australia
Date submitted for ethics approval [1] 312216 0
11/01/2023
Approval date [1] 312216 0
Ethics approval number [1] 312216 0

Summary
Brief summary
A Phase 1, Single Centre, Randomised, Double Blind, Placebo Controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, of NeuroDirect Ketamine in Healthy Adult Volunteers
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 123878 0
Dr Ofer Gonen
Address 123878 0
Dr. Ofer Gonen (Principal Investigator)
Level 5, Burnet Tower
89 Commercial Road
Melbourne, Victoria, 3004
Australia
Country 123878 0
Australia
Phone 123878 0
+61 431 614 515
Fax 123878 0
Email 123878 0
o.gonen@nucleusnetwork.com.au
Contact person for public queries
Name 123879 0
Mr Dominic Bailey
Address 123879 0
Ingenu CRO
Unit 11, 456 St. Kilda Road, Melbourne, VIC- 3004, Australia
Country 123879 0
Australia
Phone 123879 0
+61 412675026
Fax 123879 0
Email 123879 0
dom@ingenucro.com.au
Contact person for scientific queries
Name 123880 0
Mr Dominic Bailey
Address 123880 0
Ingenu CRO
Unit 11, 456 St. Kilda Road, Melbourne, VIC- 3004, Australia
Country 123880 0
Australia
Phone 123880 0
+61 412675026
Fax 123880 0
Email 123880 0
dom@ingenucro.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Commercially sensitive data


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
18055Other    Protocol Synopsis 385205-(Uploaded-16-01-2023-15-05-53)-Study-related document.pdf



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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